Pancreatic ductal adenocarcinoma (PC) is the most common malignant disease in the human pancreas. It is a highly lethal disease and the fourth leading cause of cancer deaths in the US. Fewer than 5% of people with PC live no longer than five years. One of the main reasons it has such a poor prognosis is that the majority of patients already have metastasis at the time of diagnosis, and metastasis makes PC insensitive to many chemotherapeutic drugs including gemcitabine (GEM). Thus, new ways to combat this disease are urgently needed. We discovered that Cyr61/CCN1, an extracellular protein, is overexpressed in PC cells and specimens, and its expression is correlated with disease progression and drug resistance. Moreover, Cyr61 activates sonic hedgehog (SHh) signaling, connective tissue growth factor (CTGF), mutants K-Ras and its activator MAZ/SAF-1-transcription factor in PC cells and stromal cells, all of which contribute to the development of PC as well as drug resistance. Based on these exciting preliminary findings, we now propose to use genetically engineered cell lines, genetically engineered mouse models (GEMMs) along with state-of- the-art technology to unravel if blocking Cyr61 could inhibit PC growth and drug sensitization via blocking desmoplastic reaction in PC. We propose three aims to test the hypothesis. In Aim 1, we will explore the role of Cyr61 in K-Rasmut mediated PC development and progression using GEMMs and orthotopic transplants of genetically engineered PC cell lines. In Aim 2, we will examine whether Cyr61 signaling is crucial to maintain stemness and tumorigenic activity of PC-initiating cells (PICs)/stem cells (PSCs) and dissect the down-stream signaling pathway of Cyr61 required to perform these events. Lastly, in Aim 3 we will determine the role of Cyr61 in growth of fibrous tissue (desmoplasia) during PC growth in GEMMs and orthotopic models. To test the aims, we have already standardized the use of an orthotopic human pancreatic cancer xenograft in a SCID mouse model using ultrasound guided injection of PC cells into the pancreas and high resolution imaging techniques. These techniques have already revealed many steps of the progression of this deadly disease, and they will be used along with the unique expertise of our multi-disciplinary collaborative team to explore the role of Cyr61 in pancreatic carcinogenesis. Collectively, these findings will provide knowledge of the essential functions of Cyr61, not only in development of PC, but also the critical role in tumor-stromal interactions for the development of desmoplastic reaction. This knowledge will allow dissection of the molecular mechanisms behind these vital events. Moreover, these studies will directly indicate that disruption of Cyr61-signaling would be a new therapeutic strategy against PC.